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Image / IDIBAPS-Clínic Barcelona-UB.
 10.10.2022

Leukaemia’s progression is already written from its onset at the time of diagnosis

The CNAG-CRG, based in the Barcelona Science Park, participates in a study, coordinated by researchers from IDIBAPS-Clínic Barcelona, to identify the mechanisms that determine the evolution of leukaemia, relapses following treatment, and its transformation into a very aggressive lymphoma in the final phase for some patients. The work, published in Nature Medicine, changes the view of leukaemia’s progression, opening the door to diagnosing the condition earlier and offering new strategies for its treatment.

The study, financed with a grant from the CaixaResearch call for health research of one million eurosshows that cells that cause post-treatment relapse and that give rise to the transformation of leukaemia into a very aggressive tumour can already be detected in a very small quantity at the start of the disease, many years before these complications reveal themselves clinically. The results of this work change the view held to date on how leukaemia progresses.

The article has been coordinated by Dr Elías Campo, director of IDIBAPS and head of the Molecular pathology in lymphoid neoplasms group and Dr Ferran Nadeu, post-doctoral researcher at IDIBAPS and the CIBERONC. The first co-authors of the study are, in addition to Ferran NadeuRomina Royo, researcher at the Barcelona Supercomputing Center (BSC); Ramon Massoni-Badosa, researcher at the Centro Nacional de Análisis Genómico (CNAG-CRG); Heribert Playa-Albinyana, researcher at IDIBAPS and the CIBERONC; and Beatriz García-Torre, researcher at IDIBAPS.

The Big Bang theory of cancer evolution

Until now it was believed that leukaemia progressed because its cells evolved over the course of time and transformed into more aggressive tumours because they acquired alterations to their genome in a progressive manner that made them more resistant to treatments. This new study shows that some of the leukaemia cells have already acquired these alterations right at the start of the disease, but they are only found in very small quantities. During the evolution of the disease, these more malignant cells will grow and progressively be selected, giving clinical complications many years after disease onset. “It is as if the leukaemia parent cell had engendered numerous daughter cell seeds from the onset of the disease, each of them with different alterations that will enable them to grow in the future when conditions become more suitable”, explains Elías Campo.

These observations confirm the so-called “Big Bang” theory of cancer evolution that proposes that the original malignant cell rapidly multiplies into a large number of very diverse daughter cells with numerous alterations that give rise to future complications through a selection process of those best adapted. “This new view of the disease opens the door to developing highly sensitive diagnostic tests that will enable us to detect and treat these malignant seeds many years before they can grow in an uncontrolled way”, affirms Elías Campo.

The transformation of chronic lymphatic leukaemia into a more aggressive tumour

Chronic Lymphocytic Leukaemia (CLL) is the most common leukaemia in the Western world, with a prevalence of around 5 cases per 100,000 inhabitants per year. It is usually indolent, but it can evolve into a very aggressive large B-cell lymphoma with a median survival of less than one year. This tumour transformation occurs in approximately 5-10% of patients.

For the study, the researchers set out to study in depth the alterations that determine the progression of leukaemia using blood samples obtained at different times of the disease with new highly sensitive techniques that include individual genome sequencing of thousands of cells tumours at each stage of evolution. Tumour samples were collected from 19 patients with CLL at diagnosis, at relapses after different treatments and until the final moment of transformation to aggressive lymphoma, covering up to 19 years after disease onset.

In the study, they identified the genomic alterations that determine progression and, surprisingly, found that a few cells at the earliest stage of the disease already had these alterations.

“Our study highlights that technological advances and potential clinical applications go hand-in-hand. Single-cell genomics has provided us with unprecedented discriminatory power to detect extremely infrequent cancer clones that are key for the prognosis and treatment of Richter’s transformation,” says Ramon Massoni-Badosa, researcher at the Single Cell Genomics team of the CNAG-CRG.

Ramon Massoni-Badosa (Photo CNAG-CRG).

» More information: CNAG-CRG website [+]

» Reference article: Nadeu, F., Royo, R., Massoni-Badosa, R. et al. Detection of early seeding of Richter transformation in chronic lymphocytic leukemia. Nat Med 28, 1662–1671 (2022). https://doi.org/10.1038/s41591-022-01927-8